1. Field of the Invention
The present invention relates to a new medical use of a compound for inhibiting the production or secretion of a tumor necrosis factor.
2. Related Art
A tumor necrosis factor (hereinafter abbreviated as TNF) is a peptide of 157 amino acids, having a molecular weight of about 17,000. TNF is one of cytokines produced by various cells including macrophages.
TNF had been firstly found out as a cytokine showing a cytotoxic effect on tumor. The recent studies have revealed that the activities of TNF are not only limited to tumor cells but also extended to many other normal cells. Examples of such TNF activities include suppression of the lipoprotein lipase activity in adipocytes, expression of HLA antigen on blood endothelial cells and fibroblasts, interleukin-1 production by fibroblasts or macrophages, activation of cytotoxic macrophages, suppression of CFU, production of colony stimulating factor by fibroblasts, endothelial cells or some tumor cells, inhibition of the synthesis of proteoglycans and stimulation of their resorption in cartilage, activation of neutrophils and generation of superoxide, production of procoagulant factor by blood endothelial cells, proliferation of fibroblasts, change in membrane potential of skeletal muscle, interferon .beta..sub.2 production by fibroblasts, and injury of blood endothelial cells. In these days, TNF has thus been recognized to be a cytokine which takes part broadly in vital protection through inflammation and immune response [Vassalli, P., Ann. Rev. Immunol., 10, 411-452 (1992)].
On the other hand, it is noted that continuous or excessive production of TNF rather results in vigorous actions on normal cells to cause various diseases. For example, TNF is also known as cachectin which induces cachexia in cancer or infectious diseases, involving catabolic acceleration of total metabolism to cause extreme wasting [B. Beutler, D. Greenwald, J. D. Hulmes et al., Nature, 316, 552-554 (1985), Kawakami, M., SEIKAGAKU (Biochemistry), 59, 1244-1247 (1987)].
TNF is one of causes for a septic shock; in an experiment using an antibody, its effect has been recognized [Starnes, H. F. Jr., Pearce, M. K., Tewari, A., Yim, J. H., Zou, J. C., Abrams, J. S., J. Immunol., 145, 4185-4191 (1990), Beutler, B., Milsark, I. W., Cerami, A. C., Science, 229, 869-871 (1985), Hinshaw, L. B., Tekamp-Olson, P., Chang, A. C. K. et al., Circ. Shock, 30, 279-292 (1990)].
An increased level of TNF is also observed in the synovial fluid or blood from patients with rheumatoid arthritis [Tetta, C., Camussi, G., Modena, V., Vittorio, C. D., Baglioni, C., Ann. Rheum. Dis., 49, 665-667 (1990)].
In addition, there are many other diseases of which a certain role of TNF is suspected, e.g., osteoarthritis reported by Venn, G., Nietfeld, J. J., Duits, A. J., Brennan, F. M., Arner, E., Covington, M., Billingham, M. E. J., Hardingham, T. E., Arthritis Rheum., 36 (6), 819-826 (1993); multiple sclerosis reported by Sharief, M. K., Hentges, R., N. Engl. J. Med., 325 (7), 467-472 (1991); Kawasaki disease reported by Matsubara, T., Furukawa, S., Yabuta, K., Clin. Immunol. Immunopathol., 56, 29-36 (1990); inflammatory bowel disease such as ulcerative colitis or Crohn's disease reported by Murch, S., Walker-Smith, J. A., Arch. Dis. Child, 66, 561 (1991); Maeda, M., SHOKAKI-TOMENEKI (Digestive Organ and Immunity), 22, 111-114 (1989), Behcet disease reported by Akoglu, T., Direskeneli, H., Yazici, H., Lawrence, R., J. Rheumatol., 17, 1107-1108 (1990); systemic lupus erythematosus (SLE) reported by Maury, C. P. J., Teppo, A.-M., Arthritis Rheum., 32, 146-150 (1989); graft versus host disease (GvHD) reported by Nestel, F. P., Price, K. S., Seemayer, T. A., Lapp, W. S., J. Exp. Med., 175, 405-413 (1992); multiple organ failure reported by Fujiwara, T., Kawakami, M., RINSHO-I (Clinician), 17 (10), 2006-2008 (1991); malaria reported by Grau, G. E., Fajardo, L. F., Piguet, P. F. et al., Science, 237, 1210-1212 (1987), acquired immune deficiency syndrome (AIDS) reported by Kawakami, M., Hayata K., Medical Immunology, 20, 615-620 (1990), Dezube, B. J., Pardee, A. B., J. Acquir. Immune Defic. Syndr., 5, 1099-1104 (1992); meningitis reported by Waage, A., Halstensen, A., Espevik, T., Lancet, I, 355-357 (1987); hepatitis reported by Sugano, K., KANZO (Liver), 33, 213-218 (1992), Type II diabetes mellitus reported by Hotamisligil, G. S., Shargill, N. S., Spiegelman, B. M., Science, 259, 87-91 (1993), etc.
From the above publications, it is understood that excessive production of TNF sometimes adversely affect the living body. Therefore, further investigations are desired to develop TNF inhibitors available for the treatment of these diseases.
Pentoxifylline having a methylxanthine skeleton is known as a compound showing an activity of inhibiting TNF. It is reported that this compound possesses an activity of preventing death in endotoxin-shocked mice, an activity of improving the sense of well-being or preventing a weight loss in cancer patients, an activity of preventing experimental allergic encephalomyelitis induced on an animal model, and an activity of preventing HIV-1 replication, reported by Zabel, P., Schade, F. U., Schlaak, M., Immunobiol., 187, 447-463 (1993), Dezube, B. J., Pardee, A. B. et al., Cancer Immuno. Immunother., 36, 57-60 (1993), Nataf, S., Louboutin, J. P., Chabannes, D., Feve, J. R., Muller, J. Y., Acta Neurol. Scand., 38, 97-99 (1993), Fazely, F., Dezube, B. J., Allen-Ryan, J., Pardee, A. B., Ruprecht, R. M., Blood, 77, 1653-1656 (1991). In addition, glucocorticoid, protease inhibitors, phospholipase A.sub.2 inhibitors, lipoxygenase inhibitors, platelet-aggregating factor (PAF) antagonists, radical scavengers, prostaglandin F.sub.2 or I.sub.2 and anti-TNF antibody are heretofore known as compounds or factors for showing a TNF inhibitory activity.
In the future, the role of TNF in association with diseases will be made clearer, using these low molecular compounds or antibodies. However, these compounds are accompanied by side effects due to a wide variety of the pharmacological activities. Therefore, it is desired to develop highly safe compounds based on a novel mechanism.
As a compound which is one of the effective ingredients of the composition of the present invention and has a structure close to the compounds of the present invention, there is known a compound named Eschscholtzine or crychine. The compound has the following structure: ##STR1##
Eschscholtzine is a natural substance isolated from a plant (Manske, R. H. F., Shin, K. H., Can. J. Chem., 43 (8), 2180-2182 (1965), Manske, R. H. F., Shin, K. H., Battersby, A. R., Shaw, D. F., Can. J. Chem., 43 (8), 2183-2189 (1965)). This substance is also synthesized by Barker, A. C., Battersby, A. R., J. Chem. Soc. (C), 1317-1323 (1967). It is reported that the compound has a pharmacological activity as a vasorelaxant (Ko, F.N., Wo, Y. C., Lu, S.T., Teng, C. M., J. Pharm. Pharmacol., 45 (8), 707-710 (1993)). However, no report is found on the activity of inhibiting the production or secretion of TNF as contemplated by the present invention.